Inhibition of Calcium–Calmodulin-Dependent Kinase II Suppresses Cardiac Fibroblast Proliferation and Extracellular Matrix Secretion
Inhibition of Calcium–Calmodulin-Dependent Kinase II Suppresses Cardiac Fibroblast Proliferation and Extracellular Matrix Secretion
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DOI：
10.1097/fjc.0b013e3181c9548b
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发表时间：
2010-01
影响因子：
3
通讯作者：
Wei Zhang;Dong-Qin Chen;F. Qi;Jing Wang;Wen-Yan Xiao;Weizhong Zhu
中科院分区：
文献类型：
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作者：
Wei Zhang;Dong-Qin Chen;F. Qi;Jing Wang;Wen-Yan Xiao;Weizhong Zhu
钙-钙调蛋白依赖性蛋白激酶II（CaMKII）是介导细胞内钙离子变化的主要蛋白激酶之一。它也参与心脏疾病的过程，如心脏肥大，但其对心肌纤维化的影响尚不清楚。本研究探讨是否CaMK II参与心脏成纤维细胞增殖和细胞外基质（ECM）分泌诱导血管紧张素II（AngII）或电场刺激（EFS）在培养的新生大鼠心脏成纤维细胞。通过细胞存活试验（MTT）和手动细胞计数评估心脏成纤维细胞增殖。通过基质金属蛋白酶（MMP）1、2、9和胶原I/III信使RNA表达、MMP-2、9蛋白表达以及转化生长因子β1和肿瘤坏死因子α的分泌来证明细胞基质产生。Ang Ⅱ和EFS均能促进心肌成纤维细胞增殖和ECM分泌，同时上调CaMK Ⅱ δB和δC的表达。更重要的是，CaMKII抑制剂autocamtide-2相关抑制肽（AIP 5 μM）或KN 93（0.5 μM）可抑制心脏成纤维细胞增殖，抑制转化生长因子β1和肿瘤坏死因子α的分泌，降低MMP-1、2、9和胶原I/III的信使RNA表达，降低MMP-2、9的蛋白表达。这些结果表明，CaMK Ⅱ介导的心脏成纤维细胞增殖和ECM分泌诱导的血管紧张素Ⅱ或EFS。
Calcium-calmodulin-dependent protein kinase II (CaMKII) is one of the main protein kinases mediating intracellular Ca2+ changes. It is also involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effects on myocardial fibrosis remain unclear. The present study investigates whether CaMKII is involved in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion induced by angiotensin II (AngII) or electrical field stimulation (EFS) in cultured neonatal rat cardiac fibroblasts. Cardiac fibroblast proliferation was assessed by a cell survival assay (MTT) and manual cell enumeration. Cellular matrix production was demonstrated by matrix metalloproteinases (MMP) 1, 2, 9, and collagen I/III messenger RNA expression, MMP-2, 9 protein expression, and secretion of transforming growth factor β1 and tumor necrosis factor α. Either AngII or EFS promoted cardiac fibroblast proliferation and ECM secretion, while also up-regulating expression of CaMKII δB and δC. More importantly, CaMKII inhibitors, autocamtide-2-related inhibitory peptide (AIP 5 μM) or KN93 (0.5 μM), suppressed cardiac fibroblast proliferation, inhibited the excretion of transforming growth factor β1 and tumor necrosis factor α, decreased the messenger RNA expression of MMP-1, 2, 9 and collagen I/III, and decreased the protein expression of MMP-2, 9. These results suggest that CaMKII mediates cardiac fibroblast proliferation and ECM secretion induced by either AngII or EFS.